(a) Field of the Invention
The present invention is directed to novel topical pharmaceutical gel compositions of diclofenac sodium. The topical compositions comprise at least about 10% w/w of diclofenac sodium and are suitable for twice a day application. The invention is further directed to the use of said composition for treatment of painful conditions, inflammations and/or rheumatic diseases or providing relief of the pain of osteoarthritis of joints amenable to topical treatment. Additionally, the present invention provides a method of manufacture of said composition.
(b) Description of the Related Art
Delivery of active agents across the skin or mucosal membrane is convenient, pain-free, non-invasive and circumvents problems associated with the “first pass effect”. Such transdermal or topical drug delivery is typically restricted to low molecular weight drugs and drugs with specific lipophilic/hydrophilic balance able to penetrate the stratum corneum.
Transdermal drug delivery systems enable chemical modification of the barrier properties of the skin to effectively and efficiently permit permeation thereof. Known drawbacks of transdermal delivery systems are, for example, the length of time needed for permeation, a frequent dosing regimen, and the volume size of a transdermal composition needed to transdermally deliver a sufficient therapeutic amount of the active agent.
Today, pain has become the universal disorder, a serious and costly public health issue, and a challenge for family, friends, and health care providers who must give support to the individual suffering from the physical as well as the emotional consequences of pain. In general, there are two basic types of pain: acute and chronic. Acute pain, for the most part, results from disease, inflammation, or injury to tissues. This type of pain generally comes on suddenly, for example, after trauma or surgery. In some instances, it can become chronic. Chronic pain is widely believed to represent disease itself. Chronic pain persists over a longer period of time than acute pain and is resistant to most medical treatments. It can, and often does, cause severe problems for patients.
Transdermal non-steroidal anti-inflammatory drugs (NSAIDs) offer the possibility of achieving local therapeutic benefit in pain while reducing or eliminating the risk of systemic side effects. There has been widespread interest in this approach to treating painful conditions, such as osteoarthritis (OA), but data in support of the efficacy of topical NSAIDs in the treatment of OA is limited. For instance, a study of 13 randomized placebo controlled trials of various topical NSAIDs tested specifically for use in the treatment of OA concluded that they were not generally efficacious for chronic use in OA. (Lin et al, Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomized controlled trials, BMJ, 2004).
Diclofenac (2-(2,6-dichloranilino) phenylacetic acid) is a non-steroidal anti-inflammatory drug (NSAID) used to reduce inflammation and, as an analgesic, to reduce pain. It is available in the sodium, potassium, epolamine and diethylamine salt forms in numerous dosage forms (oral tablet, oral syrup, topical gel, cataplasm, ophthalmic drop, suppository, etc.).
An example of a well-known transdermal diclofenac formulation is Voltaren® Gel 1% which comprises 1% diclofenac sodium. Voltaren® is indicated in the USA for the relief of the pain due to osteoarthritis of joints amenable to topical treatment, such as the knees and the hands. Up to 4 grams of Voltaren® gel can be applied to the lower extremities (including the knees, the ankles, and the feet) 4 times daily so that up to not more than 16 grams daily of Voltaren® Gel 1% is applied to any single joint of the lower extremities. Up to 2 grams of Voltaren® Gel 1% can also be applied to the upper extremities (which include the elbows, the wrists and the hands) 4 times daily so that up to not more than 8 grams daily of Voltaren® Gel 1% is applied to any single joint of the upper extremities. Overall, the total dose of Voltaren® Gel 1% should not exceed 32 grams per day over all affected joints. Neither the total amount (up to 32 grams per day) nor the frequency of application (4 times a day) are satisfactory from a patient perspective.
U.S. Pat. No. 7,335,379 discloses formulations for transdermal or transmucosal administration of active agents, such as diclofenac, containing an alkanol, a polyalcohol, a monoalkyl ether of diethylene glycol and a fatty alcohol with a fatty alcohol content of up to 2%.
U.S. Pat. No. 4,543,251 discloses an external gel formulation containing 0.3 to 3% w/w of diclofenac sodium having good stability.
PCT Application Publication No. 2014009241 discloses diclofenac gel formulations containing 1% and 3% diclofenac sodium, C2 to C4 alkanol, monoalkyl ether of diethylene glycol and fatty alcohol.
U.S. Pat. No. 7,132,452 discloses topical formulations containing a NSAID, particularly diclofenac for alleviating the pain/inflammation associated with infection caused by the herpes virus. The amount of diclofenac in the formulation can be 1-10% w/w of the entire formulation. The '452 patent discloses that the formulation provides complete relief on application for seven days.
EP Pat. No. 1,890,687 discloses topical gel formulations of diclofenac sodium for relief of pain and inflammation. According to the patent the formulation may contain up to 10% w/w of diclofenac.
U.S. Pat. Nos. 4,575,515 and 4,652,557 disclose topical NSAID compositions, one of which, consisting of 1.5% diclofenac sodium, 45.5% dimethylsulphoxide, 11.79% ethanol, 11.2% propylene glycol, 11.2% glycerine, and water, has been shown to be effective in chronic OA treatment.
None of the prior art references disclose or suggest topical gel formulations containing a high amount of diclofenac sodium, let alone its therapeutic benefits on twice daily application. Moreover, the known formulation containing lower amounts of diclofenac sodium requires frequent dosing of three to four times a day to achieve efficacy in chronic conditions, such as OA, which can increase the risk of skin irritation.
There remains a need for topical compositions of diclofenac containing at least about 10% w/w of diclofenac sodium which are effective for treatment of painful conditions, such as inflammation. The compositions should provide fast and effective treatment for alleviating symptoms relating to acute or chronic pain, including that of osteoarthritis of joints, and require only twice daily application to achieve equal or more therapeutic benefits than those achieved by multiple applications of currently known 1% w/w or 3% w/w diclofenac gel formulations.